1,1-Dihalo-1-(methylsufonyl)methanesulfonamides

ABSTRACT

The compounds of the formula CH3SO2CX2SO2NR1R2 in which X is chloro or bromo and R1 and R2 independently are hydrogen, 1 to 16 carbon atom alkyl, phenyl or substituted phenyl and together with the nitrogen atom represent a heterocycle which may contain an oxygen atom or another nitrogen atom in the heterocycle. The compounds are prepared by reacting the corresponding 1-(methylsulfonyl)methanesulfonamide with alkali metal hypohalite in the presence of an organic solvent. The compounds have antimicrobial activity.

United States Patent [1 1 Goralski et al.

[ 1,l-DIHALO-l-(METHYLSUFONYL)ME- THANESULFONAMIDES [75] Inventors: Christian T. Goralski; Thomas C.

Klingler, both of Midland, Mich.

[73] Assignee: The Dow Chemical Company,

Midland, Mich.

[22] Filed: Apr. 1, 1974 [21] Appl. No.: 456,942

Related US. Application Data [62] Division of Ser. No. 322,434, Jan. 10, 1973, Pat. No.

[52] US. Cl 260/556 A; 424/321; 260/2471; 260/293.85; 260/326.82 [51] Int. Cl. C07C 143/75 1 [58] Field of Search 260/556 A [56] References Cited UNITED STATES PATENTS 1/1975 Goralski et al 260/556 AR X OTHER PUBLICATIONS CA 65: 18464 b, A Sulfene Stable at 40C., Opitz et al., 1966.

[ Dec. 16, 1975 Primary ExaminerR. V. Hines Assistant ExaminerThomas A. Waltz Attorney, Agent, or Firml; C. Kenneth Bjork ABSIRACT The compounds of the formula 4 Claims, N0 Drawings l,l-DIHALO-1-(METHYLSUFONYL)ME- THANESULFONAMIDES CROSS REFERENCE TO RELATED APPLICATION This is a division of application Ser. No, 322, 434 filed Jan. 10, 1973, now US. Pat. No. 3,865,822.

SUMMARY OF THE INVENTION This invention concerns compounds represented by the formula CH SO CX SO NR R wherein X represents chloro or bromo and R and R2 independently represent hydrogen, 1 to 16 carbon atoms alkyl, i.e., from l, to 2, to 3, to 4, to 5, to 6, to 7, to 8, to 9, to 10, to 11, to 12, to 13, to 14, to 15, to 16 carbon atom alkyl, phenyl or substituted phenyl and together with the nitrogen atom represent a heterocycle which maycontain an oxygen atom in the heterocycle. In the specification and claims, substituted phenyl represents phenyl having lower alkyl, lower alkoxy, chloro or bromo substitution; the term heterocyclic ring designates a pyrrolidinyl, morpholinyl or a piperidinyl heterocyclicring system; and lower alkyl and lower alkoxy represent 1 to 4 carbon alkyl and alkoxy groups, respectively.

The compounds of the invention are prepared by mixing a corresponding 1 -(methy1su1fonyl)methanesu1- fonamide with an alkali metal hypochlorite or hypobromite, advantageously formed in situ from an alkali metal hydroxide and chlorine or bromine in substantially 2 molar proportions of the halogen to 1 molar proportion of the l-(methylsulfonyl)-methanesulfonamide in aqueous medium, advantageously in the presence of a solvent for the sulfonamide, i.e., dioxane or other water-miscible ether. Reaction is allowed to proceed for about 30 minutes to about 1 hour at substantially 5to 40C. The product is separated from the reaction medium and recrystallized from a lower alkanol, preferably methanol or ethanol.

In practice, the 1-(methylsulfonyl)methanesulfonamide is slurried in a solvent such as dioxane or other water-miscible ether and to it is added aqueous alkali metal hydroxide, the resulting solution is cooled in an ice bath and bromine added thereto dropwise. After a short reaction time of about 30 minutes, the solvent is removed in vacuo and the solid product is filtered off and recrystallized from methanol or ethanol. Alternatively, the l-(methylsu1fonyl)methanesulfonamide is added to an aqueous solution of sodium hydroxide maintained at about 5C. and to it is gradually added bromine with stirring, continued for about 30 minutes at about 5 to C. The product is taken up in hot methanol or ethanol, cooled to about room temperature, filtered and recrystallized. In another alternative, the 1-(methylsulfony1)methanesulfonamide is dissolved in a solvent such as ,dioxane and to it a requisite amount of aqueous 5% sodium hypochlorite or sodium hypobromite is added. After a short reaction time of about 30 minutes, the solution is acidified with concentrated mineral acid, advantageously the corresponding hydrohalic acid, the solvent is removed in vacuo, the crude product slurried in aqueous methanol or ethanol, filtered and the purified product crystallized out.

The following examples describe representative specific embodiments and the best modes contemplated by the inventors of carrying out their invention. In the ex- 2 amples, temperature is given in centigrade degrees. The compounds are identified by elemental analysis and by nuclear magnetic resonance.

EXAMPLE 1 1,l-Dibromo-l-(methylsu1fonyl)methanesulfonamide EXAMPLE 2 l 1 -Dibromo-N-methyll (methylsulfonyl )methanesulfonamide A solution of 4.32 g. (0.108 mol) of sodium hydroxide in 150 m1. of water is cooled to 3C. and 10 g. (0.0535 mol) of N-methyl-1-(methylsulfonyl)methanesulfonamide dissolved in it. Then add dropwise 17.3 g. (0.108 mol) of bromine over a 15 minute period. After stirring for 15 minutes more, the product is filtered off. Recrystallization from aqueous methanol gives 15.74 g. (85.5% yield) of white crystals; m.p. 128129.5C.

Anal. Calcd. for C 1-I Br NO S C, 10.44; H, 2.04; Br, 46.32; N, 4.06; S, 18.59. Found: C, 11.03; H, 1.96; Br, 47.0 i 0.2; N, 4.34; S, 18.60.

EXAMPLE 3 1 1 -Dibromo-N,N-dimethyl-2-(methylsulfony1)methanesulfonamide A slurry of 5.0 g. (25 mmol) of N,N-dimethyl-1-(methylsulfonyl)methanesulfonamide, 40 ml. of water and 8.1 g. of bromine is cooled to 5C. in an ice bath. A solution of 2.1 g. of sodium hydroxide in 30 ml. of water is then added dropwise, maintaining the temperature below 10C. After an hour, the product is filtered off. The aqueous layer is extracted with chloroform to remove unreacted starting material. Recrystallization of the product from aqueous ethanol gives 6.76 g. yield) of the dibromo product as white crystals, m.p. ll9-l20C.

Anal. Calcd. for C 1-I Br NO S C, 13.38; H, 2.53; N, 3.90; S, 17.86; Br, 44.51. Found: C, 13.90, 13.81; H, 2.55, 2.58; N, 4.15, 4.05; S, 17.97, 18.19; Br, 45 i: .2.

EXAMPLE 4 1 ,1-Dibromo-N-hexy1- 1-(methylsulfonyl)methanesulfonamide A solution of 3.2 g. of sodium hydroxide in m1. of water is cooled to 2C. and 10.0 g. (39 mmol) of N-hexyl-l-(methylsulfonyl)methanesulfonamide is added. Then 13.0 g. of bromine is added at 0C. After 30 minutes the product is fltered off and recrystallized from aqueous ethanol to give 8.58 g. (53% yield) of waxy white crystals; m.p. 71.5-73C.

Anal. Calcd. for C H Br NO S C, 23.14; H, 4.13; N, 3.37; S, 15.45; Br, 38.49. Found: C, 23.32; H, 4.00; N, 3.63; S, 16.12; Br, 38.2 :02.

EXAMPLE l 1 -Dibromo-N-dodecyl- 1 -(methylsulfonyl )methanesulfonamide 5 To a slurry of g. (29.3 mmol) of N-dodecyl-l-(methylsulfonyl)methanesulfonamide in 150 ml. of dioxane is added 2.34 g. (58.6 mmol) of sodium hydroxide in 50 ml. of water. The resultingsolution is cooled in an ice bath and 10.0 g. of bromine added thereto dropwise.

EXAMPLE 6 4-((Dibromo(methylsulfonyl )methyl)sulfonyl)-morpholine To a solution of 8.8 g. (0.22 mol) of sodium hydroxide in 500 ml. of water at 5C. add 24.3 g. (0.1 mol) of 4'-( (methylsulfonyl )methyl )sulfonyl )morpholine Then add 40 g. (0.25 mol) of bromine and stir continuously for 30 minutes at 510C. The product is taken up in 1600 ml. of hot ethanol and cooled to 25C. Filtration removes unreacted startingmaterial. The filtered solution is concentrated and chilled to give g. of dibromo product (63% yield) as white needles; m.p. 125-126C.

Anal. Calcd. for C H Br NO S C, 17.97; H, 2.76; N, 3.49; S, 15.99; Br, 39.84. Found: C, 18.18; H, 2.69; N, 3.67; S, 16.03; Br, 40.0 i 0.2.

EXAMPLE 7 4-((Dichloro(methylsulfonyl)methyl)sulfonyl)-morpholine 1 Gram of 4-(((methy1sulfonyl)methyl)sulfonyl)- morpholine is dissolved in 100 ml. of dioxane and 25 ml. of 5% aqueous sodium hypochlorite is added. After 30 minutes the solution is acidified with concentrated l-lCl acid. The dioxane is removed in vacuo and the product washed with water to remove NaCl and recrys- :allized from absolute ethanol to give white crystals, n.p. 1 15117C.

Anal. Calcd. for C H Cl NO S C, 23.08; H, 3.55; 31, 22.71; N, 4.49; S, 20.54. Found: C, 23.00; H, 3.51; :1, 22.80; N, 4.55; S, 20.60.

EXAMPLE 8 1,1,2, 4', 6, Pentabromol methylsulfonyl )-methan esulfonanilide To a solution of 5 g. (0.125 mol) of sodium hydroxde in 250 ml. of water at 5C. add 5 g. (0.02 mol) of .-(methylsulfonyl)methanesulfonanilide. Then add g. (0.125 mol) of bromine with vigorous stirring. After .8 hours the pink product is filtered off and recrystalized from chloroform/hexane to give a 49% yield of )inkish white crystals, m.p. 202-203C.

Anal. Calcd. for C H Br NO S C, 14.93; H, 0.94; 3r, 62.06; N, 2.17; S, 9.96. Found: C, 15.22; H, 1.04; 3r, 61.3 i 0.6; N, 2.35; S, 10.00.

EXAMPLE 9 1 1 -Dibromo-N-methyl- 1 -(methylsulfonyl )methanesulfonanilide To a solution of 10 g. (38 mmol) of Nmethyl-l-(methylsulfonyl)methanesulfonanilide in 100 ml. of dioxane add 3.1 g. of sodium hydroxide (77.5 mmol) in ml. of water. After 30 minutes add 12.4 g. (76 mmol) of bromine and stir for 63 hours. The product is filtered off and recrystallized from methanol to give 8.4 g. of fine white crystals; m.p. 150l51.5C.

Anal. Calcd. for C H Br NO S C, 25.67; H, 2.63; N, 3.32; S, 15.23; Br, 37.95. Found: C, 25.63; H, 2.49; N, 3.39; S, 14.83, 14.89; Br, 39.5 :t 0.2.

EXAMPLE 1 0 1,1-Dibromo-l-(methylsulfonyl)-N,N-(diphenyl)methanesulfonamide To a solution of 10 g. (30.8 mmol) of N,N-diphenyll-(methylsulfonyl)methanesulfonamide, 2.46 g. of sodium hydroxide, 250 ml. of dioxane and 80 ml. of water add 10.4 g. (65 mmol) of bromine and stir for 3 hours. The solvent is removed in vacuo and the residue slurried with 300 ml. of water and filtered. Recrystallization of the product from 2 liters of ethanol gives 10.4 g. of white needles; m.p. l89l90C. (dec.).

Anal. Calcd. for C H Br NO S C, 34.80; H, 2.71; N, 2.90; S, 13.27; Br, 33.07. Found: C, 34.91; H, 2.56; N, 3.00; S, 13.23; Br, 32.5 :02.

EXAMPLE 1 1 1-( Dichloro( methylsulfonyl )methyl )sulfonyl )-pipe ridine 4 Grams of 1-(((methylsulfonyl)methyl)sulfony1)- piperidine is dissolved in 200 ml. of dioxane and ml. of 5% aqueous sodium hypochlorite is added. After 30 minutes the solution is acidified with concentrated HCl acid. The dioxane is removed in vacuo, the product washed with water to remove NaCl and recrystallized from absolute ethanol to give 2.77 g. of white crystals, m.p. 91-93C.

Anal. Calcd. for C-,H Cl NO S C, 27.10; H, 4.22; C1, 22.86; N, 4.51; S, 20.67. Found: C, 26.80; H, 4.05; Cl, 22.70; N, 4.46; S, 20.50.

The compounds of the invention are useful as antimicrobials for the control of bacteria, fungi and yeasts. For such uses, the compounds can be employed in an unmodified form or dispersed on a finely divided solid and employed as dusts. Such mixtures can also be dispersed in water with or without the aid of a surface-active agent and the resulting aqueous suspensions employed as sprays. In other procedures, the products can be employed as active constituents in solvent solutions, oil-in-water or water-in-oil emulsions or aqueous dispersions. The augmented compositions are adapted to be formulated as concentrates and subsequently diluted with additional liquid or solid adjuvants to produce the ultimate treating compositions. Good results are obtained when employing compositions containing antimicrobial concentrations and usually from about 100 to 1,000 parts by weight of one or more of the compounds per million parts of such compositions.

In representative operations, compounds of the present invention were tested for their activity as antimic robials using conventional agar dilution tests. The following Table presents results expressed as ppm of toxicant of the examples to provide 100% growth inhibition of phenyl having lower alkyl, of l to 4 carbon atoms, the indicated organisms. lower alkoxy of l to 4 carbon atoms, chloro or bromo TABLE I MINIMUM GROWTH INHIBITOR! CONCENTRATION, p.p.m.

Example 8:: Ca Ec Pa St Mp Tm Bs Cp Aa Pp Cf Ci Ts At Rn 3 100 I00 100 I00 I00 100 100 100 100 100 100 100 100 100 too 100 4 100 I00 100 100 100' 100 100 I00 100 100 100 100 100 100 I00 100 5 l00 I00 100 100 100 100 100 100 100 100 I00 100 100 100 100 100 Cp=C. pelliculosa Sa=S. aureus Ca=C. albicans Aa=A. aerogenes Ec=E. coli Pp=P. pullulans Pa=Pseudomonas aeruginosa Cf=C. fragans St=S. typhosa Ci=C. ips' I Mp=M. phlei Ts=Trichoderma Species P-42 Tm=T. mentagrophytes At=A. terreus Bs,=B. subtilis Rn=R. nigricans substitution at least one of which is phenyl or substi- The l-(methylsulfonyl)methanesulfonamides are tuted phenyl. v prepared by the procedure of G. Opitz e.a., Angew, 2; The compound of claim 1 which is 1,1,2, 4, 6'-

Chem., Int. Ed, 5, 594 (1966).. pentabromo-l-(methylsulfonyl)methanesulfonanilide. What is claimed is: 3. The compound of claim 1 which is l,1-dibromo-N- 1. A compound represented by the formula methyl-l(methylsulfonyl)methanesulfonanilide.

CH SO CX SO NR R wherein X represents chloro or 4. The compound of claim 1 which is 1,1-dibromo-lbromo and R and R independently represent hydro- (methylsulfonyl)-N,N-(diphenyl)methanesulfonamide. gen, 1 to 16 carbon atom alkyl, phenyl or substituted 

1. A COMPOUND REPRESENTED BY THE FORMULA CH3SO2CX2SO2NR1R2 WHEREIN X REPRESENTS CHLORO OR BROMO AND R1 AND R2 INDEPENDENTLY REPRESENT HYDROGEN, 1 TO 16 CARBON ATOM ALKYL, PHENYL OR SUBSTITUTED PHENYL HAVING LOWER ALKYL, OF 1 TO 4 CARBON ATOMS, LOWER ALKOXY OF 1 TO 4 CARBON ATOMS, CHLORO OR BROMO SUBSTITUTION AT LEAST ONE OF WHICH IS PHENYL OR SUBSTITUTED PHENYL.
 2. The compound of claim 1 which is 1,1,2'', 4'', 6''-pentabromo-1-(methylsulfonyl)methanesulfonanilide.
 3. The compound of claim 1 which is 1,1-dibromo-N-methyl-1-(methylsulfonyl)methanesulfonanilide.
 4. The compound of claim 1 which is 1,1-dibromo-1-(methylsulfonyl)-N,N-(diphenyl)methanesulfonamide. 